Our earliest program goes back to the PI's laboratory at the University of Pittsburgh. At first, it was entirely directed to charting advances in organic synthesis both as to logic and methodology. It then evolved into a broader effort at Yale Univeristy seeking to use advances in synthesis to arrive at small molecule natural products (SMNPs) and to exploit its total syntheses of such SMNPs. When our laboratory moved to NYC and bifurcated between Memorial Sloan-Kettering Cancer Center and the Department of Chemistry at Columbia Univeristy, HL 25848 was transferred to Columbia. Two cancer driven grants support our work at MSKCC. The renewal we seek at Columbia is the last we shall undertake on HL 25848. While our laboratory remains fully productive and competitive, we recognize the appropriateness of making way for a new generation of scientists, who will pursue exciting new directions. Our goals in seeking this renewal are several. First, we are convinced that it will foster research which will be intellectually valuable and also of interest of the translational level. Moreover, being the sole source of support for our Columbia program, it will enable us to bring our program here to an orderly conclusion while meeting commitments to various graduate students and postdoctorals, both for their research and in their career enhancement. The program is distributed among ten projects which, we think, can be mastered in the indicated time frame. Projects D1-D4 envision major new departues from conventional thinking about the Diels Alder reaction. Project D1 utilizes the Diels Alder reaction to reach systems hitherto constructed through carbonyl condensation reactions. Project D2 combines the DA reaction with other chemistry to reach trans fused junctions, whereas the classical DA reaction traditionally is seen as a route to cis fusions. Project D3 achieves the paradigm shift in the context of the intramolecular Diels Alder reaction (IMDA). Project D4 utilizes the advances from D1 through D3 to accomplish a new total synthesis of highly active corticosteroids. Projects D5 through D8 have strong elements of pharmaceutical relevance. Thus, project D5 seeks to find development candidates in the context of SMNPs with neurotrophic activity, the ultimate goal being application to neurodegenerative diseases. Project D6 builds from our synthesis of a compound in red ginseng. We have moved on to obtain a candidate structure for carcinoprevention. Projects D7 and D8 build from our recently completed total syntheses of ET-743 and pluraflavin A which led to some interesting and unexpected SAR findings. Project D9 involves, hopefully, the completion of the total synthesis of tricholomalide A following significant advances, though much remains to be done. Project D10 envisions a fresh total synthesis (based on new chemistry) of jiadifenin, analogs of which seem very promising for future development. PUBLIC HEALTH RELEVANCE: Our program seeks to study potential advances in organic synthesis and to apply such advances to the elaboration and study of small molecule natural products (SMNP) or natural product congeners of novel biological activity. In HL 25848, we will be engaged at three levels, i) a program directed to synthetic methodology; ii) another effort will be directed to medicinal chemistry, and iii) a program directed to two challenging problems in total synthesis of bioactive SMNPs.